Information on the following diseases can be found in the Related Disorders section of this report:

• Atelosteogenesis Type II
• Achondrogenesis Type IB
• Pseudodiastrophic Dysplasia
• Achondroplasia
• Arthrogryposis Multiplex Congenita
• Associated Congenital Disorders (General)

The symptoms and physical findings associated with diastrophic dysplasia may be extremely variable, differing in range and severity even among affected family members (kindreds). However, in all individuals with the disorder, there is abnormal development of bones and joints of the body (skeletal and joint dysplasia).

During normal development before birth (embryonic and fetal development) as well as development during early childhood, cartilage in many areas of the body is gradually replaced by bone (ossification). In addition, a layer of cartilage (epiphyseal cartilage [growth plate]) separates the shafts (diaphyses) of long bones (e.g., bones of the arms and legs) from their ends (epiphyses), allowing long bones to grow until the cartilage is no longer present. In those affected by diastrophic dysplasia, however, there is delayed growth before and after birth (prenatal and postnatal growth retardation), the development of the ends of the long bones (epiphyses) is irregular, and the ossification of the epiphyses is delayed. Thus, affected newborns and children typically have markedly short, bowed arms and legs and short stature (short-limbed dwarfism). In addition, in such cases, growth failure is typically progressive, in part due to absence of the "growth spurt" that usually occurs during puberty. The severity of such growth failure may vary greatly from case to case, including among affected siblings.

Due to abnormalities of skeletal development, infants and children with diastrophic dysplasia also have additional distinctive malformations of bones of the hands, feet, and other areas of the body. For example, the first bone within the body of each hand (first metacarpals) may be unusually small, short, and "oval shaped." As a result, the thumbs deviate away (abduction) from the body ("hitchhiker thumbs"). In addition, other fingers may be abnormally short (brachydactyly) and joints between particular bones of the fingers (proximal interphalangeal joints) may become fused (symphalangism), causing limited flexion and restricted movement (reduced mobility) of the finger joints. In some cases, bones of the wrists may also be malformed due to premature ossification.

Infants with the disorder also typically have severe foot deformities (talipes or "clubfeet") due to abnormal fusion and deviation of bones within the body of each foot (metatarsals). In most cases, the heels turn outward (talipes valgus) while the fore part of each foot deviates inward (metatarsus adductus). In other infants, the soles of the feet may be flexed (talipes equinus) and, in some cases, the heels may also turn inward (talipes equinovarus). The great toes, like the thumbs, may also deviate away (abduction) from the body.

In addition to having limited flexion of finger joints, many affected infants and children also experience partial dislocation (subluxation) and/or complete dislocation of particular joints of the body. For example, in many cases, dislocations of the knees and hips occur upon weightbearing. Affected individuals may also have abnormally loose and/or stiff joints; experience limited extension of joints at the elbows and/or knees; and/or develop permanent flexion and immobilization (contracture) of certain joints (e.g., knees). Due to joint and bone abnormalities such as those affecting the feet, many individuals with diastrophic dysplasia have a tendency to walk on tiptoe. In addition, affected individuals may be predisposed to degenerative changes (osteoarthrosis) of particular joints (e.g. of the hips), resulting in pain with use of the joint, tenderness, stiffness, and, in some cases, deformity.

Many infants with diastrophic dysplasia also have abnormalities of bones within the spinal column (vertebrae). For example, in most affected infants, there may be incomplete closure of vertebrae (spina bifida occulta) within the neck area and the upper portion of the back (lower cervical and upper thoracic vertebrae) and/or abnormal narrowing of portions of the vertebrae of the lower back (interpedicular narrowing in lumbar vertebrae). During the first year of life, some infants may begin to develop progressive abnormal sideways curvature of the spine (scoliosis). In addition, during adolescence, individuals with diastrophic dysplasia may also develop abnormal front-to-back curvature of the spine (kyphosis), particularly affecting vertebrae of the neck region (cervical vertebrae). In severe cases, progressive kyphosis may result in difficulties breathing (respiratory distress). Some individuals with the disorder may also be prone to experiencing partial dislocation of joints between the central areas (bodies) of cervical vertebrae (cervical subluxation), potentially resulting in compression of the spinal cord. (This cylindrical structure of nerve tissue extends from the lower portion of the brain and is located inside the central canal within the spinal column [spinal cavity].) Such spinal cord injury may result in muscle weakness (paresis) or paralysis and/or life-threatening complications.

Most newborns with diastrophic dysplasia also have or develop fluid-filled sacs (cysts) within the outer, visible portions of the ears (pinnae). Within approximately two to five weeks after birth, the pinnae become swollen and inflamed. When such swelling and inflammation subside, the pinnae remain unusually thick, hard, and abnormal in shape. The abnormal areas of tissue (lesions) may gradually accumulate deposits of calcium salts (calcification) and eventually be replaced by bone (ossification). Although affected infants may experience associated abnormal narrowing (stenosis) of the external ear canal (external auditory canal), hearing is usually normal. However, according to reports in the literature, other affected infants and children may experience hearing impairment due to such auditory canal stenosis or abnormal fusion or absence of the three tiny bones (auditory ossicles) in the middle ear that conduct sound to the inner ear.

Some infants with diastrophic dysplasia also have characteristic malformations of the head and facial (craniofacial) area, such as an unusually high, prominent forehead; abnormal smallness of the jaws (micrognathia); and/or a broad, highly arched roof of the mouth (palate) or incomplete closure of the palate (cleft palate). Cleft palate has been reported to occur in anywhere from 25 to 60% of affected infants, and may cause difficulties with feeding and/or breathing. In addition, in some infants with diastrophic dysplasia, abnormalities of supportive connective tissue (cartilage) within the windpipe (trachea), voice box (larynx), and air passages in the lungs (bronchi) may cause abnormal narrowing (e.g., laryngotracheal stenosis) and collapse of such airways. In such cases, life-threatening complications such as respiratory obstruction and difficulties breathing (respiratory distress) may result. However, in many cases nasal speech (hyponasality) occurs as a result of the abnormally shaped vocal tract.

Approximately one third of infants and children with diastrophic dysplasia also have dental abnormalities, such as abnormally small teeth and dental crowding. In addition, in some cases, affected infants may have benign, reddish purple growths in the midportion of the face (midline frontal hemangioma) due to an abnormal distribution of tiny blood vessels (capillaries). Some individuals with the disorder may also have additional symptoms and physical findings.
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Diastrophic dysplasia is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal copy of the gene and one mutated copy of the gene, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Parents of some individuals with diastrophic dysplasia have been closely related by blood (consanguineous). If both parents carry an altered gene for the disorder, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.

A gene responsible for diastrophic dysplasia, known as DTDST (for "diastrophic dysplasia sulfate transporter" gene), has been located on the long arm (q) of chromosome 5 (5q32-q33.1). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, 5q32 refers to band 32 on the long arm of chromosome 5.

The symptoms and findings associated with diastrophic dysplasia are thought to result due to abnormalities in the formation of cartilage, thus affecting skeletal development. Early during normal embryonic development, the skeleton mainly consists of cartilage that is gradually replaced by bone (ossification). After birth, many bones of the skeleton still consist primarily of cartilage that will eventually ossify. However, researchers suspect that certain changes (mutations) of the DTDST gene result in abnormalities of cartilage cells (chondrocytes) and the substance (matrix) that lies between such cells, ultimately causing the symptoms and findings associated with the disorder. For example, in individuals with diastrophic dysplasia, the growth plate of long bones may contain an abnormal distribution of cartilage cells (chondrocytes) and abnormal fibrous and cystic areas within its matrix.

As discussed below (see "Affected Population"), diastrophic dysplasia is particularly frequent in Finland. Genetic analysis has revealed that a specific mutation, designated as "DTDST(Fin)," is present in affected members of many Finnish families (kindreds) and suggests that a single mutation event may have occurred in a common ancestor (i.e., founder mutation) in the past. However, in some Finnish kindreds, the disorder has been shown to result from different DTDST gene mutations (DTD-causing alleles) that do not descend from the common ancestral (founder) mutation. In addition, different mutations of the DTDST gene have been identified in some non-Finnish individuals with the disorder.
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Diastrophic dysplasia affects males and females in equal numbers.
Although the disorder is extremely rare, the percentage of carriers in certain groups is high. In Finland, 1-2% of the general population are carriers and a total of 183 cases have been diagnosed, with a prevalence ratio of 1 in 30,000. Diastrophic dysplasia has been observed in most white populations

Symptoms of the following disorders may be similar to those of diastrophic dysplasia. Comparisons may be useful for a differential diagnosis:

Atelosteogenesis type II, also known as neonatal osseous dysplasia I, is a rare genetic disorder caused by abnormal changes (mutations) of the disease gene (DTDST) that is also responsible for diastrophic dysplasia (allelic disorder). Although the disorder has many symptoms and findings similar to those associated with diastrophic dysplasia, it is typically more severe. Atelosteogenesis type II is characterized by marked shortness of the arms and legs (micromelia), outward deviation (abduction) of the thumbs and great toes, and severe deformity of the feet (talipes or "clubfeet") in which the soles are flexed and the heels are turned inward (talipes equinovarus). Additional characteristic features include an unusually small chest (thorax), abnormal flatness of certain bones in the spinal column (vertebrae), abnormal sideways curvature of the spine (scoliosis), front-to-back curvature of vertebrae within the neck area of the spine (cervical kyphosis), and/or incomplete closure of the roof of the mouth (cleft palate). Due to abnormalities of cartilage within the voice box (larynx), windpipe (trachea), and air passages in the lungs (bronchi), affected infants may experience narrowing of the larynx (laryngeal stenosis), abnormal softness of cartilage in the trachea and bronchi (tracheobronchomalacia), and underdevelopment of the lungs (pulmonary hypoplasia). Such abnormalities may result in collapse of such airways, causing life-threatening complications shortly after birth, such as respiratory obstruction and difficulties breathing (respiratory distress). Atelosteogenesis type II is inherited as an autosomal recessive trait.

Achondrogenesis type IB is a rare genetic disorder that is also thought to be caused by mutations of the disease gene responsible for diastrophic dysplasia (allelic disorder). According to reports in the literature, the disorder is more severe than diastrophic dysplasia and atelosteogenesis type II. Achondrogenesis type IB is characterized by marked shortness of the arms and legs (micromelia) and short stature (short-limbed dwarfism), abnormally thin ribs, and a susceptibility to rib fractures. Additional characteristic features include impaired ossification of vertebrae of the lower back (lumbar vertebrae); the five fused bones forming the large triangular bone (sacrum) of the lower spine (sacral vertebrae); and certain bones that form the hip bones (pubic and ischial bones). Achondrogenesis type IB is inherited as an autosomal recessive trait.

Pseudodiastrophic dysplasia is a rare genetic disorder characterized by abnormally short arms and legs and short stature (short-limbed dwarfism) and severe deformities of the feet (talipes or "clubfeet") that tend to respond well to surgical treatment and physical therapy. Additional features may include dislocations of certain joints in the fingers (proximal interphalangeal joints), dislocations of the elbows, flattening of the central regions of bones in the spinal column (platyspondyly), abnormal sideways curvature of the spine (scoliosis), and/or other abnormalities. In contrast to individuals with diastrophic dysplasia, the first bones within the body of each hand (first metacarpals) have a normal appearance and the outer, visible portions of the ears (pinnae) do not experience the inflammation and cystic enlargement often seen in those with diastrophic dysplasia in the first weeks of life. Pseudodiastrophic dysplasia is inherited as an autosomal recessive trait.

Achondroplasia is a rare genetic disorder characterized by distinctive abnormalities of the head and facial (craniofacial) area; unusually short upper arms and legs and short stature (short-limbed dwarfism); and short hands with fingers that assume a "trident" or three-pronged position during extension. Affected individuals may also have limited extension of the elbows and hips, bowing of the legs, and abnormally increased curvature of the bones of the lower spine (lumbar lordosis). In addition, many individuals with achondroplasia have an abnormally enlarged brain (macrencephaly), a prominent forehead (frontal bossing), and a flat (depressed) nasal bridge. In some cases, affected individuals may experience inhibition of the normal flow of cerebrospinal fluid (CSF), potentially causing increased pressure on brain tissue. In most cases, achondroplasia appears to occur randomly (sporadically) due to new genetic changes (mutations). In other cases, the disorder may be inherited as an autosomal dominant trait. (For more information on this disorder, choose "Achondroplasia" as your search term in the Rare Disease Database.)

Arthrogryposis multiplex congenita is a group of disorders present at birth (congenital) that are characterized by limited movement or immobility of several joints and partial or complete replacement of muscle with fibrous tissue in affected areas. Affected joints may be permanently flexed or extended in various fixed postures (joint contractures). In many cases, the term arthrogryposis multiplex congenita refers to a form of the disorder in which joint contractures result in abnormal extension of the elbows, flexion of the wrists, and internal rotation of the shoulders. In addition, many affected individuals may have severe clubfoot (talipes equinovarus), a deformity in which the heel is turned inward and the sole is flexed (plantar flexion). Additional associated abnormalities may include a rounded face and a slightly small jaw. This form of the disorder appears to occur randomly (sporadically), for unknown reasons. Another form of the disorder, known as a distal arthrogryposis (type 1), may be characterized by joint contractures primarily affecting the hands and feet (distal limbs). Such contractures result in characteristic positioning including permanent flexion (camptodactyly) and overlapping of fingers, deviation of fingers toward the "pinky" side of the hand (ulnar deviation), clenching of the fists, and clubfeet. This form of the disorder is inherited as an autosomal dominant trait. The causes of other forms of arthrogryposis multiplex congenita are variable. (For more information on this disorder, choose "arthrogryposis multiplex congenita" as your search term in the Rare Disease Database.)

There may be additional disorders that are characterized by growth delays before and after birth (prenatal and postnatal growth retardation); abnormally short arms and legs and short stature (short-limbed dwarfism); distinctive malformations of bones of the fingers and hands; clubfeet; partial (subluxation) or complete dislocation and/or permanent flexion and immobilization (contractures) of certain joints; abnormal progressive curvature of the spine (e.g., scoliosis and/or kyphosis); and/or other abnormalities similar to those potentially associated with diastrophic dysplasia. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Diagnosis
In some families with a previous history of diastrophic dysplasia, it is possible that the disorder may be detected before birth (prenatally) during early pregnancy (e.g., first trimester) based upon the results of specialized genetic (i.e., DNA marker) testing. In addition, in some cases, the disorder may be detected during mid pregnancy (e.g., second trimester) through fetal ultrasonography, a specialized imaging technique in which sound waves are used to create an image of the developing fetus. In such cases, diagnosis is most easily established when a clear family history is present. During fetal ultrasonography, a diagnosis of diastrophic dysplasia may be considered due to detection of certain characteristic findings, such as marked shortening of bones of the fingers (phalanges), arms, and legs; abnormal deviation (abduction) of the thumbs ("hitchhiker thumbs") and great toes; severe deformities of both feet (talipes or "clubfeet"); and/or other findings.

In most cases, diastrophic dysplasia is diagnosed and/or confirmed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specializing tests, such as advanced imaging techniques. For example, specialized x-ray studies such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to detect, confirm, and/or characterize certain skeletal abnormalities that may be associated with diastrophic dysplasia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves are used to create cross-sectional images of organs and structures in the body.

Specialized diagnostic testing (i.e., audiological tests) may also be performed to help detect hearing deficits that may occur in some children with diastrophic dysplasia.

Treatment
The treatment of diastrophic dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; dental specialists (orthodontists); specialists who assess and treat hearing problems (audiologists); and/or other health care professionals.

Specific therapies for the treatment of diastrophic dysplasia are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate preventive or corrective treatment of respiratory obstruction and distress that may result due to certain abnormalities potentially associated with the disorder (e.g., laryngotracheal stenosis). In addition, special supportive measures may be used to help ensure an appropriate intake of nutrients in infants who experience feeding difficulties due to cleft palate. In some cases, surgical procedures may be performed to correct malformations resulting in breathing and/or feeding difficulties. The specific procedures performed will depend upon the location, severity, and combination of such anatomical abnormalities.

In addition, various orthopedic techniques, including surgery, may also be used to help prevent, treat, and/or correct certain skeletal deformities associated with diastrophic dysplasia. In some cases, physical therapy in combination with surgical and supportive measures may be helpful in improving an affected individual's ability to walk and perform other movements (mobility). According to the medical literature, although the foot deformities (i.e., talipes or clubfeet) associated with the disorder may be resistant to treatment, early, persistent therapy may be helpful in achieving beneficial results. In addition, because particular skeletal changes associated with diastrophic dysplasia are progressive (e.g., kyphosis) and, in some cases, may lead to severe complications (e.g., respiratory distress, compression of the spine, potential paresis or paralysis), physicians may perform ongoing monitoring to ensure prompt detection of and appropriate preventive and/or corrective measures for such abnormalities.

In affected children with dental abnormalities, braces (orthodontics), dental surgery, and/or other corrective procedures may be undertaken to correct such malformations. Steroid injections and/or other measures may also be used to help decrease the ear deformity that often affects infants with the disorder.

Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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The Chorionic Villus Sampling Birth Defects Registry has been established to collect information about individuals exposed to chorionic villus sampling who developed hemangiomas. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). For more information, contact:

Caroline McGuirk, MPH, Coordinator
Chorionic Villus Sampling Birth Defects Registry
Tel: (888) 287-0738
E-mail: mcguirk@mgh.harvard.edu

ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). Victor A. McKusick, Editor; Johns Hopkins University, Last Edit Date 6/7/00, Entry Number 222600; Last Edit Date 12/3/96, Entry Number 600972; Last Edit Date 11/24/98, Entry Number 256050; Last Edit Date 1/26/98, Entry Number 264180; Last Edit Date 1/27/99, Entry Number 100800.

TEXTBOOKS
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Beighton P, ed. McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis, MO: Mosby-Year Book, Inc.; 1993:594-601.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:533-35.

JOURNAL ARTICLES
Bieganski T, et al. Diastrophic dysplasia with severe primary kyphosis and 'monkey wrench' appearance of the femora. Australas Radiol. 2000;44:450-53.

Hastbacka J, et al. Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Eur J Hum Genet. 1999;7:664-70.

Vaara P, et al. Health-related quality of life in patients with diastrophic dysplasia. Scand J Public Health. 1999;27:38-42.

Makitie O, et al. Growth in diastrophic dysplasia. J Pediatr. 1997;130:641-46.

Hall BD. Diastrophic dysplasia: extreme variability within a sibship. Am J Med Genet. 1996;63:28-33.

Rossi A, et al. Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. Hum Genet. 1996;98:657-61.

Karlstedt E, et al. Phenotypic features of dentition in diastrophic dysplasia. J Craniofac Genet Dev Biol. 1996;16:164-73.

Qureshi F, et al. Histopathology of fetal diastrophic dysplasia. Am J Med Genet. 1995; 56:300-03.

Hastbacka J, et al. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 1994;78:1073-87.

Hastbacka J, et al. Prenatal diagnosis of diastrophic dysplasia with polymorphic DNA markers. J Med Genet. 1993;30:265-68.

Peltonen JI, et al. Cementless hip arthroplasty in diastrophic dysplasia. J Arthroplasty. 1992;7[suppl]:369-76.

Poussa M, et al. The spine in diastrophic dysplasia. Spine. 1991;16:881-87.

Hastbacka J, et al. Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc Natl Acad Sci USA. 1990;87:8056-59.

Lamy M, et al. Le nanisme diastrophique. Presse Med. 1960;68:1977-80.

INTERNET:
Diastrophic Dysplasia
eMedicine - Diastrophic Dysplasia : Article by Shital Parikh, MBBS, MS
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